Endothelial β-Catenin Signaling Is Required for Maintaining Adult Blood-Brain Barrier Integrity and Central Nervous System Homeostasis

Circulation. 2016 Jan 12;133(2):177-86. doi: 10.1161/CIRCULATIONAHA.115.015982. Epub 2015 Nov 4.


Background: The blood-brain barrier (BBB) formed by brain endothelial cells interconnected by tight junctions is essential for the homeostasis of the central nervous system. Although studies have shown the importance of various signaling molecules in BBB formation during development, little is known about the molecular basis regulating the integrity of the adult BBB.

Methods and results: Using a mouse model with tamoxifen-inducible endothelial cell-restricted disruption of ctnnb1 (iCKO), we show here that endothelial β-catenin signaling is essential for maintaining BBB integrity and central nervous system homeostasis in adult mice. The iCKO mice developed severe seizures accompanied by neuronal injury, multiple brain petechial hemorrhages, and central nervous system inflammation, and all had postictal death. Disruption of endothelial β-catenin induced BBB breakdown and downregulation of the specific tight junction proteins claudin-1 and -3 in adult brain endothelial cells. The clinical relevance of the data is indicated by the observation of decreased expression of claudin-1 and nuclear β-catenin in brain endothelial cells of hemorrhagic lesions of hemorrhagic stroke patients.

Conclusions: These results demonstrate the prerequisite role of endothelial β-catenin in maintaining the integrity of adult BBB. The results suggest that BBB dysfunction secondary to defective β-catenin transcription activity is a key pathogenic factor in hemorrhagic stroke, seizure activity, and central nervous system inflammation.

Keywords: blood–brain barrier; brain; cerebrovascular disorders; endothelium; intracranial hemorrhages.

Publication types

  • Research Support, N.I.H., Extramural
  • Video-Audio Media

MeSH terms

  • Adult
  • Aged
  • Animals
  • Ataxia / etiology
  • Basal Ganglia / metabolism*
  • Blood-Brain Barrier / physiology*
  • Brain / pathology
  • Cerebral Hemorrhage / etiology
  • Cerebral Hemorrhage / metabolism*
  • Claudin-1 / biosynthesis
  • Claudin-1 / deficiency
  • Claudin-1 / genetics
  • Claudin-3 / biosynthesis
  • Claudin-3 / genetics
  • Crosses, Genetic
  • Cytokines / biosynthesis
  • Cytokines / genetics
  • Down-Regulation
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Female
  • Gene Expression Regulation / drug effects
  • Gene Knockdown Techniques
  • Genes, Reporter
  • Homeostasis
  • Humans
  • Hyperesthesia / etiology
  • Inflammation
  • Male
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Organ Specificity
  • RNA Interference
  • Seizures / etiology
  • Tight Junctions
  • Transgenes
  • beta Catenin / biosynthesis
  • beta Catenin / deficiency*
  • beta Catenin / genetics
  • beta Catenin / physiology*


  • CLDN1 protein, human
  • CTNNB1 protein, human
  • CTNNB1 protein, mouse
  • Claudin-1
  • Claudin-3
  • Cldn1 protein, mouse
  • Cldn3 protein, mouse
  • Cytokines
  • beta Catenin